Process for the preparation of pyrazolopyridine derivatives

ABSTRACT

The invention provides a process for preparing a compound of formula (I) and pharmaceutically acceptable derivatives thereof in which: R 0  is halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy substituted by one or more fluorine atoms, or O(CH 2 ) n NR 4 R 5 ; R 1  and R 2  are independently selected from H, C 1-6 alkyl, C 1-6 alkyl substituted by one or more fluorine atoms, C 1-6 alkoxy C 1-6 hydroxyalkyl, SC 1-6 alkyl, C(O)H, C(O)C 1-6 alkyl, C 1-6 alkylsulphonyl, C 1-6 alkoxy substituted by one or more fluorine atoms, O(CH 2 ) n CO 2 C 1-6 alkyl, O(CH 2n SC 1-6 alkyl, (CH 2 ) n NR 4 R 5 , (CH 2 ) n SC 1-6 alkyl or C(O)NR 4 R 5 ; with the proviso that when R 0  is at the 4-position and is halogen, at least one of R 1  and R 2  is C 1-6 alkylsulphonyl, C 1-6 alkoxy substituted by one or more fluorine atoms, O(CH 2 ) n CO 2 C 1-6 alkyl, O(CH 2 ) n SC 1-6 alkyl, (CH 2 ) n NR 4 R 5  or (CH 2 ) n SC 1-6 alkyl, C(O)NR 4 R 5 ; R 3  is C 1-6 alkyl or NH 2 ; R 4  and R 5  are independently selected from H, or C 1-6 alkyl or, together with the nitrogen atom to which they are attached, form a 4-8 membered saturated ring; and n is 1-4; which comprises oxidizing a corresponding compound of formula (II) or an isomer thereof.

[0001] This invention relates to a process for the preparation ofpyrazolopyridazine derivatives and to intermediates for use therein.

[0002] Pyrazolopyridazine derivatives of formula (I)

[0003] and pharmaceutically acceptable derivatives thereof in which:

[0004] R⁰ is halogen, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxy substituted byone or more fluorine atoms, or O(CH₂)_(n)NR⁴R⁵;

[0005] R¹ and R² are independently selected from H, C₁₋₆alkyl, C₁₋₆alkylsubstituted by one or more fluorine atoms, C₁₋₆alkoxy, C₁₋₆hydroxyalkyl,SC₁₋₆alkyl, C(O)H, C(O)C₁₋₆alkyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxysubstituted by one or more fluorine atoms, O(CH₂)_(n)CO₂C₁₋₆alkyl,O(CH₂)_(n)SC₁₋₆alkyl, (CH₂)_(n)NR⁴R⁵, (CH₂)_(n)SC₁₋₆alkyl or C(O)NR⁴R⁵;with the proviso that when R⁰ is at the 4-position and is halogen, atleast one of R¹ and R² is C₁₋₆alkylsulphonyl, C₁₋₆alkoxy substituted byone or more fluorine atoms, O(CH₂)_(n)CO₂C₁₋₆alkyl,O(CH₂)_(n)SC₁₋₆alkyl, (CH₂)_(n)NR⁴R⁵ or (CH₂)_(n)SC₁₋₆alkyl, C(O)NR⁴R⁵;

[0006] R³ is C₁₋₆alkyl or NH₂;

[0007] R⁴ and R⁵ are independently selected from H, or C₁₋₆alkyl or,together with the nitrogen atom to which they are attached, form a 4-8membered saturated ring;

[0008] and n is 1-4;

[0009] are disclosed in international patent application publication no.WO99/12930, incorporated herein by reference.

[0010] By pharmaceutically acceptable derivative is meant anypharmaceutically acceptable salt, solvate or ester, or salt or solvateof such ester, of the compounds of formula (I), or any other compoundwhich upon administration to the recipient is capable of providing(directly or indirectly) a compound of formula (I) or an activemetabolite or residue thereof.

[0011] It will be appreciated that, for pharmaceutical use, the saltsreferred to above will be the physiologically acceptable salts, butother salts may find use, for example in the preparation of compounds offormula (I) and the physiologically acceptable salts thereof.

[0012] Suitable pharmaceutically acceptable salts of the compounds offormula (I) include acid addition salts formed with inorganic or organicacids, preferably inorganic acids, e.g. hydrochlorides, hydrobromidesand sulphates.

[0013] The term halogen is used to represent fluorine, chlorine, bromineor iodine.

[0014] The term ‘alkyl’ as a group or part of a group means a straightor branched chain alkyl group, for example a methyl, ethyl, n-propyl,i-propyl, n-butyl, s-butyl or t-butyl group.

[0015] The compounds of formula (I) are potent and selective inhibitorsof COX-2. They are of interest for use in human and veterinary medicine,particularly in the treatment of the pain (both chronic and acute),fever and inflammation of a variety of conditions and diseases.

[0016] Several processes for the preparation of the compounds of formula(I) are disclosed in WO99/12930.

[0017] The present invention provides a particularly advantageousprocess of preparing compounds of formula (I), not hitherto specificallydisclosed, which comprises oxidation of a correspondingdihydro-pyrazolopyridazine.

[0018] Accordingly, in a first aspect, the instant invention provides aprocess for the preparation of a compound of formula (I) which comprisesoxidising under conventional conditions a compound of formula (II)

[0019] wherein R⁰ to R³ are as defined for formula (I).

[0020] Conveniently the oxidation is effected in a solvent, such as ahalogenated alkane (e.g. dichloromethane); at ambient to elevatedtemperature, such as from 20° C. to reflux (e.g. at about 25° C.); andin the presence of a catalyst, such as activated carbon, or a transitionmetal catalyst (e.g. palladium on activated carbon). Alternatively, thecatalyst may be replaced by an oxidising agent, such as a source ofoxygen (e.g. air), or iodine.

[0021] The process according to the invention is surprisinglyadvantageous, being easy to carry out and proceeding in good yield.

[0022] As will be appreciated by those skilled in the art, thepreparation of pharmaceutically acceptable derivatives of formula (I)may conveniently be effected by a process which comprises oxidisingunder conventional conditions a corresponding derivative of formula(II).

[0023] In another aspect the invention provides a process for preparinga compound of formula (I) where R⁰ is at the 3- or 4-position of thephenyl ring, as defined in formula (I).

[0024] In another aspect the invention provides a process for preparinga compound of formula (I) where R¹ is at the 6-position of thepyridazine ring, as defined in formula (I).

[0025] In another aspect the invention provides a process for preparinga compound of formula (I) where R⁰ is F, C₁₋₃alkyl, C₁₋₃alkoxy,C₁₋₃alkoxy substituted by one or more fluorine atoms, or O(CH₂)₁₋₃NR⁴R⁵;or, more preferably, R⁰ is F, C₁₋₃alkoxy or C₁₋₃alkoxy substituted byone or more fluorine atoms.

[0026] In another aspect the invention provides a process for preparinga compound of formula (I) where R¹ is C₁₋₄alkylsulphonyl, C₁₋₄alkoxysubstituted by one or more fluorine atoms, O(CH₂)₁₋₃CO₂C₁₋₄alkyl,O(CH₂)₁₋₃SC₁₋₄alkyl, (CH₂)₁₋₃NR⁴R⁵, (CH₂)₁₋₃SC₁₋₄alkyl or C(O)NR⁴R⁵ or,when R⁰ is C₁₋₆alkyl, C₁₋₆alkoxy, O(CH₂)_(n)NR⁴R⁵, may also be H; or,more preferably, R¹ is C₁₋₄alkylsulphonyl, C₁₋₄alkoxy substituted by oneor more fluorine atoms or, when R⁰ is C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxysubstituted by one or more fluorine atoms, or O(CH₂)_(n)NR⁴R⁵, may alsobe H.

[0027] In another aspect the invention provides a process for preparinga compound of formula (I) where R² is H.

[0028] In another aspect the invention provides a process for preparinga compound of formula (I) where R³ is methyl or NH₂.

[0029] In another aspect the invention provides a process for preparinga compound of formula (I) where R⁴ and R⁵ are independently C₁₋₃alkylor, together with the nitrogen atom to which they are attached, form a5-6 membered saturated ring.

[0030] In another aspect the invention provides a process for preparinga compound of formula (I) where n is 1-3, more preferably 1 or 2.

[0031] In another aspect the invention provides a process for preparingone group of compounds of formula (I) (group A) wherein: R⁰ is F,C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkoxy substituted by one or more fluorineatoms, or O(CH₂)_(n)NR⁴R⁵; R¹ is C₁₋₄alkylsulphonyl, C₁₋₄alkoxysubstituted by one or more fluorine atoms, O(CH₂)_(n)CO₂C₁₋₄alkyl,O(CH₂)_(n)SC₁₋₄alkyl, (CH₂)_(n)NR⁴R⁵, (CH₂)_(n)SC₁₋₄alkyl or C(O)NR⁴R⁵or, when R⁰ is C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkoxy substituted by one ormore fluorine atoms, or O(CH₂)_(n)NR⁴R⁵, may also be H; R² is H; R³ ismethyl or NH₂; R⁴ and R⁵ are independently C₁₋₃alkyl or, together withthe nitrogen atom to which they are attached, form a 5-6 memberedsaturated ring; and n is 1-3.

[0032] In another aspect the invention provides a process for preparinganother group of compounds (group A1) wherein R⁰ is F, methyl,C₁₋₂alkoxy, OCHF₂, or O(CH₂)_(n)NR⁴R⁵; R¹ is methylsulphonyl, OCHF₂,O(CH₂)_(n)CO₂C₁₋₄alkyl, O(CH₂)_(n)SCH₃, (CH₂)_(n)NR⁴R⁵, (CH₂)_(n)SCH₃ orC(O)NR⁴R⁵ or, when R⁰ is methyl, C₁₋₂alkoxy, OCHF₂, orO(CH₂)_(n)N(CH₃)₂, may also be H; R² is H; R³ is methyl or NH₂; R⁴ andR⁵ are both methyl or, together with the nitrogen atom to which they areattached, form a 5-6 membered saturated ring; and n is 1-2.

[0033] In another aspect the invention provides a process for preparinga compound of formula (I) within group (group A2) wherein R⁰ is F,C₁₋₃alkoxy or C₁₋₃alkoxy substituted by one or more fluorine atoms; R¹is C₁₋₄alkylsulphonyl, C₁₋₄alkoxy substituted by one or more fluorineatoms or, when R⁰ C₁₋₃alkoxy or C₁₋₃alkoxy substituted by one or morefluorine atoms, may also be H; R² is H; and R³ is methyl or NH₂.

[0034] In another aspect the invention provides a process for preparinga compound of formula (I) within groups A, A1 and A2, wherein R⁰ ispreferably at the 3- or 4-position of the phenyl ring and R² is at the6-position of the pyridazine ring.

[0035] In another aspect the invention provides a process for preparingthe compound2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazineand pharmaceutically acceptable derivatives thereof.

[0036] Compounds of formula (II), including derivatives corresponding topharmaceutically acceptable derivatives of formula (I), may be preparedby any method known in the art for the preparation of compounds ofanalogous structure.

[0037] The present invention provides a particularly advantageousprocess for the preparation of compounds of formula (II), as illustratedin Scheme 1 that follows. The reaction conditions and reagents mentionedin Scheme 1 are by way of example only. In scheme 1, R⁰ to R³ are asdefined for formula (I) above; Ph is phenyl; and X is a counterion.

[0038] Ref 1H. Zimmer, J. P. Bercz, Liebigs Ann. Chem. 1965, 686,107-114, incorporated herein by reference.

[0039] Ref 2 Friedel Crafts acylation in the presence of a Lewis acid(e.g. AlCl₃).

[0040] Ref 3 Suitable inorganic bases include alkali hydroxides (e.g.NaOH); suitable organic bases include amines (e.g.N,N,N,N-tetramethylethylenediamine).

[0041] It will be appreciated by those skilled in the art that theimines of formula (III) prepared from the ethanones of formula (V) neednot necessarily be isolated and may be employed in situ in thepreparation of compounds of formula (II).

[0042] The compounds of formula (II) themselves need not necessarily beisolated and may be employed in situ in the preparation of compounds offormula (I), as described hereinabove.

[0043] Counterion X⁻ in the N-aminopyridazinium salts of formula (IV) isconveniently a halide (e.g. I⁻) or, more preferably, hexafluorophosphate(PF₆ ⁻). N-Aminopyridazinium hexafluorophosphate salts of formula (IV)are novel and their use according to Scheme 1 is surprisinglyadvantageous. Thus N-aminopyridazinium hexafluorophosphate salts offormula (IV) are easily prepared and enable the conversion of ethanonesof formula (V) to compounds of formula (II) via imines of formula (III)to proceed easily and in high yield.

[0044] Accordingly, in a further aspect the invention providesN-aminopyridazinium hexafluorophosphate salts of formula (IV) wherein R⁰to R³ are as defined for formula (I) above, in particularN-aminopyridazinium hexafluorophosphate.

[0045] It will be appreciated by those skilled in the art that compoundsof formula (II) may exist as a number of isomers, for example, asfollows:

[0046] It will be further appreciated by those skilled in the art thatsuch isomers may under certain conditions exist as an equilibratingmixture.

[0047] It will be still further appreciated by those skilled in the artthat the compounds of formula (II) contain at least one chiral centre,designated by * therein, and that such compounds exist in the form of apair of optical isomers (i.e. enantiomers).

[0048] It is to be understood that the present invention encompasses allisomers of the compounds of formula (II) and pharmaceutically acceptablederivatives thereof, including all positional, geometric, tautomeric,optical and diastereomeric forms, and mixtures thereof (e.g. racemicmixtures).

[0049] N-Aminopyridazinium halides of formula (IV) are either knowncompounds or may be prepared by literature methods such as thosedescribed in, for example, Y Kobayashi et al, Chem Pharm Bull, (1971),19(10), 2106-15; T. Tsuchiya, J. Kurita and K. Takayama, Chem. Pharm.Bull. 28(9) 2676-2681 (1980); and K Novitskii et al., Khim GeterotskilSoedin, 1970 2, 57-62; all incorporated herein by reference.

[0050] N-Aminopyridazinium hexafluorophosphates of formula (IV) may beprepared by reacting the corresponding N-aminopyridazinium sulphate withhexafluorophosphoric acid or a suitable salt thereof (e.g. potassiumhexafluorophosphate or ammonium hexafluorophosphate). The aforementionedsulphates may be prepared from pyridazine by conventional means.

[0051] Compounds of formula (VII) are either known compounds or may beprepared by literature methods such as those described in, for example,H Forrest, A Fuller, J Walker, J Chem Soc., 1948, 1501; R Dohmori, ChemPharm Bull., 1964, (12), 591; and R Bromilow, K Chamberlain, S Patil,Pestic. Sci., 1990, (30), 1.

[0052] Compounds of formulae (VI), (VIII) and (X) are either knowncompounds or may by prepared from known compounds by conventionalchemistry.

[0053] As will be appreciated by those skilled in the art it may benecessary or desirable at any stage in the synthesis of compounds offormula (I) to protect one or more sensitive groups in the molecule soas to prevent undesirable side reactions.

[0054] The protecting groups used in the preparation of compounds offormula (I) may be used in conventional manner. See, for example, thosedescribed in ‘Protective Groups in Organic Synthesis’ by Theodora W.Green and Peter G M Wuts, second edition, (John Wiley and Sons, 1991),incorporated herein by reference, which also describes methods for theremoval of such groups.

[0055] Certain intermediates described above are novel compounds, and itis to be understood that all novel intermediates herein form furtheraspects of the present invention. Compounds of formula (II), (III) and(V), especially those compounds wherein R⁰ is ethoxy, R¹ and R² are H,and R³ is methyl, are key intermediates and represent a particularaspect of the present invention.

[0056] Conveniently, compounds of formula (I) are isolated followingwork-up in the form of the free base. Pharmaceutically acceptable acidaddition salts of the compounds of formula (I) may be prepared usingconventional means.

[0057] Solvates (e.g. hydrates) of a compound of formula (I) may beformed during the work-up procedure of one of the aforementioned processsteps.

[0058] When a particular isomeric form of a compound is desired therequired isomer may conveniently be separated using preparative highperformance liquid chromatography (h.p.l.c.).

[0059] The following Examples illustrate, but do not in any way limit,the invention. All temperatures are in ° C. Flash column chromatographywas carried out using Merck 9385 silica. Thin layer chromatography (Tlc)was carried out on silica plates. NMR was carried out on a Bruker 400MHz spectrometer, unless otherwise stated. Chemical shifts are given,with respect to tetramethylsilane as internal chemical shift reference,in δ ppm. The following abbreviations are used: Me, methyl; Et, ethyl;Ph, phenyl; IMS, industrial methylated spirits; TMEDA,N,N,N,N-tetramethylethylenediamine; DCM, dichloromethane; TFA,trfluoroacetic acid; s, singlet; d, doublet; t, triplet and m,multiplet.

EXAMPLE 1

[0060] N-Aminopyridazinium Hexafluorophosphate

[0061] A solution of hydroxylamine-O-sulfonic acid (73.4 g) in water (80mL) and a separate solution of potassium carbonate (65.5 g) in water (80mL) were added concurrently dropwise to a solution of pyridazine (40.0g) in water (120 mL) at 50° C., maintaining a reaction mixture pH of3.5-4.0. The reaction mixture was then heated at 40° C. for 2 hours togive a solution of N-aminopyridazinium sulfate, which was subsequentlycooled to 20° C. and filtered. The filtrate was added dropwise to asolution of potassium hexafluorophosphate (91.9 g) in water (460 mL) at50° C. The resulting suspension was slowly cooled to 5° C. over a 2 hourperiod, stirred for 30 minutes and the product isolated by filtration.The filtercake was washed portionwise with water (320 mL) and theproduct dried in vacuo at 40° C. to give the title compound as a whitecrystalline solid (69.9 g, 58%).

[0062]¹H-NMR (CDCl₃); δ8.11(1H) m, J=8.4 Hz, J=5.4 Hz; δ8.46(1H) m,J=8.4 Hz, J=6.4 Hz; δ9.09(1H) d, J=6.4 Hz; δ9.24(1H) m, J=5.4 Hz;δ9.84(2H, NH₂) s.

[0063]¹⁹F-NMR (CDCl₃); δ70.55 (6F, PF₆ ⁻) d, J _(P—F)=711 Hz.

EXAMPLE 2

[0064] N-Aminopyridazinium Hexafluorophosphate

[0065] By using ammonium hexafluorophosphate (50.9 g) in water (50 mL),the title compound was obtained as a white crystalline solid (51.7 g,68.7% based on pyridazine) in the manner of Example 1 and wasspectroscopically identical thereto.

EXAMPLE 3

[0066] N-Aminopyridazinium Hexafluorophosphate

[0067] By using a 60% w/w aqueous solution of hexafluorophosphoric acid(15.2 g), the title compound was obtained as a white crystalline solid(10.4 g, 68.8% based on pyridazine) in the manner of Example 1 and wasspectroscopically identical thereto.

EXAMPLE 4

[0068] 1-(4-Ethoxyphenyl)-2-[4-(methylsulfonyl)phenyl]ethanone

[0069] To a stirred suspension of 4-methylsulfonylphenylacetic acid ¹(10 g) in DCM (80 mL) was added dimethylformamide (0.18 mL). The mixturewas heated to 30° C., treated with thionyl chloride (3.6 mL) and stirredfor 1½ hours. The resulting solution was cooled to 15° C., treated withgranular aluminium chloride (11.8 g) and stirred for further 15 minutes.Ethoxybenzene (7.1 mL) was added and the resultant mixture was warmed to20° C. and stirred for 2 hours. The reaction mixture was cooled to 10°C. and treated dropwise with IMS (17 mL). The mixture was then dilutedwith DCM (120 mL) and water (60 mL) was then added over 20 minutes. Themixture was warmed to 30° C. and the layers separated. The organic layerwas washed with 5M hydrochloric acid (2×40 mL), saturated sodiumbicarbonate solution (40 mL) and then concentrated by distillation atatmospheric pressure to 40 mL. The mixture was cooled to 22° C. and agedfor 18 hours. The product was isolated by filtration, washed withDCM:iso-octane (1:1, 2×20 mL) and dried in vacuo at 40° C. to give thetitle compound as a white crystalline solid (10.3 g, 69%). MH⁺ 319

[0070]¹H-NMR (CDCl₃) δ: 7.98(m, J=9.1 Hz, 2H, 2× p-di-substitutedaromatic CH); 7.91(m, J=8.5 Hz, 2H, 2× p-di-substituted aromatic CH);7.47(m, J=8.5 Hz, 2H, 2× p-di-substituted aromatic CH); 6.95(m, J=9.1Hz, 2H, 2× p-di-substituted aromatic CH); 4.34(s, 2H, CH₂); 4.12(q,J=7.2 Hz, 2H, ethoxy-CH₂); 3.05(s, 3H, CH₃); 1.45(t, J=7.2 Hz, 3H,ethoxy-CH₃).

EXAMPLE 5

[0071] A solution of1-(4ethoxyphenyl)-2-[4-(methylsulfonyl)phenyl]ethanone (0.5 g) in DCM(10 mL) was treated with triethylamine (0.22 mL) followed by titaniumtetrachloride (0.52 mL). To the resultant deep red solution was addedN-aminopyridazinium iodide ¹ (0.26 g) and the mixture was heated underreflux for 18 hours. The reaction mixture was cooled to about 20° C. andtreated dropwise with water (5 mL). The organic phase was washed withsodium hydroxide solution (2N, 5 mL), concentrated to dryness and asample of the resulting crude solid analysed by HPLC-NMR. ColumnInertsil ODS-2 20 cm × 0.46 cm (5 μM) Flow rate 1 mL/minute Detection UVand NMR (Bruker DRX600 NMR Spectrometer) Time (min) MeCN + 0.05% v/v TFA(%) D₂O + 0.05% v/v TFA (%)  0 10 90 10 10 90 20 90 10 25 90 10 26 10 90

[0072] Two peaks were observed and characterised as follows:

[0073] a) Rt 9.74 min: The imine of formula (III) wherein R⁰ is OEt, R¹and R² are H and R³ is Me:

[0074]¹H-NMR (MeCN/D₂O) δ9.45(1H) d, J=6 Hz; δ9.36(1H) d, J=6 Hz;δ8.60(1H) m, J=8 Hz, J=6 Hz; δ8.44(1H) m, J=8 Hz, J=6 Hz; δ8.03(2H) d,J=8.2 Hz; δ7.79(2H) d, J=8.2 Hz; δ7.42(2H) d, J=8.2 Hz; δ7.05(2H) d,J=8.2 Hz; δ4.28(2H) s; δ4.13(2H) q, J=7.0 Hz; δ3.12(3H) s; δ1.35(3H) t,J=7.0 Hz; M 396

[0075] b) Rt 15.17 min:2-(4-Ethoxyphenyl)-3-(4-methanesulfonyl-phenyl)-3,3a-dihydro-pyrazolo[1,5-b]pyridazine

[0076] (co-elutes with1-(4-ethoxyphenyl)-2-[4-(methylsulfonyl)phenyl]ethanone)

[0077]¹H-NMR (CH₃CN/D₂O) δ8.02 (2H) d, J=8.8 Hz; δ7.87 (2H) d, J=7.6 Hz;δ7.51(2H) d, J=7.6 Hz; δ7.02 (2H) d, J=8.8 Hz; δ6.72 (1H) m; δ5.85 (1H)m; δ5.56 (1H) m; δ4.87 (1H) d, J=10.6 Hz; δ4.69 (1H) m; δ4.12 (2H) q,ethyl (partially obscured under water peak); δ3.12 (3H) s; δ1.37 (3H) t,J=7.0 Hz; MH⁺ 396.

[0078] The skilled artisan will appreciate that the title compound mayunder certain conditions exist as an equilibrating mixture (discussedabove on pages 7 & 8).

EXAMPLE 6

[0079]2-(4-Ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine(i)2-(4-Ethoxyphenyl)-3-(4-methanesulfonyl-phenyl)-3,3a-dihydro-pyrazolo[1,5-b]pyridazine

[0080] A solution of1-(4-ethoxyphenyl)-2-(4-methanesulfonyl-phenyl)-ethanone (0.25 g) in DCM(5 mL) was treated with triethylamine (0.1 mL) followed by titaniumtetrachloride (0.26 mL). To the resultant deep red solution was addedN-aminopyridazinium iodide (0.26 g) and the mixture was heated underreflux for 18 hours. The reaction mixture was cooled to 20° C. andtreated dropwise with water (5 mL). The organic phase was separated,washed with sodium hydroxide solution (2N, 5 mL) and concentrated invacuo to dryness. A sample of the residue was analysed by massspectrometry, displaying a single major component, MH⁺ 396,corresponding to the title compound. The skilled artisan will appreciatethat the title compound may under certain conditions exist as anequilibrating mixture (discussed above on pages 7 and 8).

[0081] (ii)2-(4-Ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine

[0082] The residue from Example 6(i),2-(4-ethoxyphenyl)-3-(4-methanesulfonyl-phenyl)-3,3a-dihydro-pyrazolo[1,5-b]pyridazine,was redissolved in DCM (5 mL) and palladium on carbon (10% wt, 0.25 g)was added. The mixture was heated under reflux for 18 hours, whereuponanalysis of the mixture by mass spectrometry showed the presence of amain component, MH⁺ 394, corresponding to the title compound. Thereaction mixture was purified directly by silica gel chromatography(ethyl acetate/cyclohexane 2:1) to give the title compound as a whitesolid (0.181 g, 59%).

[0083] MH⁺ 394

[0084]¹H-NMR (CDCl₃) δ: 8.30(d of d, J=4.4 Hz, J=1.9 Hz, 1H, aromaticCH); 7.98(m, J=8.5 Hz, 2H, 2× p-di-substituted aromatic CH); 7.91(d ofd, J=9.1 Hz, J=1.9 Hz, 1H, aromatic CH); 7.58(m, J=8.5 Hz, 2H, 2×p-di-substituted aromatic CH); 7.55(m, J=8.8 Hz, 2H, 2× p-di-substitutedaromatic CH); 7.07(d of d, J=9.1 Hz, J=4.4 Hz, 1H); 6.89(m, J=8.8 Hz,2H, 2× p-di-substituted aromatic CH); 4.06(q, J=7.0 Hz, 2H, ethoxy-CH₂);3.13(s, 3H, CH₃); 1.43(t, J=7.0 Hz, 3H, ethoxy-CH₃).

EXAMPLE 7

[0085]2-(4-Ethoxyphenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine

[0086] Titanium tetrachloride (12.0 mL) was added to a stirredsuspension of 1-(4-ethoxyphenyl)-2-(4-methanesulfonyl-phenyl)-ethanone(10.0 g), N-aminopyridazinium hexafluorophosphate (8.3 g) andtriethylamine (4.4 mL) in DCM (200 mL) at 20° C. and the reactionmixture heated at 40° C. for 4.5 hours. The reaction mixture was cooledto 28° C., treated dropwise with TMEDA (2.4 mL) and heated at 40° C. for18 h to give a solution of the imine of Example 5(a). The reaction wascooled to 25° C., treated dropwise with further TMEDA (21.3 mL) andstirred at 25° C. for 3 hours to give a solution of(2-(4-ethoxyphenyl)-3-(4-methanesulfonyl-phenyl-3,3a-dihydro-pyrazolo[1,5-b]pyridazine).Iodine (8.0 g) was added and the reaction mixture stirred at 25° C. for20 hours. IMS (25 mL) was added dropwise and the reaction mixture wasthen concentrated to 16 volumes by distillation at atmospheric pressure.The reaction was cooled to 30° C. and then treated with 3.33Mhydrochloric acid (150 mL). The organic phase was separated and theaqueous phase further extracted with DCM (60 mL). The combined organicextracts were treated with charcoal (5 g) and concentrated to 5 volumesby distillation at atmospheric pressure. The concentrate was dilutedwith ethyl acetate (200 mL) and reconcentrated to 5 volumes bydistillation at atmospheric pressure. The concentrate was furtherdiluted with ethyl acetate (150 mL), heated to 60° C., filtered througha pad of celite, and the celite filtercake washed with warm ethylacetate (100 mL). The combined filtrate and washes were heated to 60°C., washed with 2M sodium hydroxide (50 mL), 20% aqueous sodiumthiosulfate (2×50 mL), water (2×50 mL) and concentrated to 4 volumes bydistillation at atmospheric pressure. The slurry was stirred overnightat ambient temperature and then at 5° C. for 3.5 hours. The product wasisolated by filtration, the filtercake washed with cold ethyl acetate(20 mL) and the product dried in vacuo at 45° C. to give the titlecompound as a pale brown crystalline solid (8.8 g, 71%). MH⁺ 394

[0087]¹H-NMR (CDCl₃) δ: 8.30(d of d, J=4.4 Hz, J=1.9 Hz, 1H, aromaticCH); 7.98(m, J=8.5 Hz, 2H, 2× p-di-substituted aromatic CH); 7.91(d ofd, J=9.1 Hz, J=1.9 Hz, 1H, aromatic CH); 7.58(m, J=8.5 Hz, 2H, 2×p-di-substituted aromatic CH); 7.55 (m, J=8.8 Hz, 2H, 2×p-di-substituted aromatic CH); 7.07(d of d, J=9.1 Hz, J=4.4 Hz, 1H);6.89(m, J=8.8 Hz, 2H, 2× p-di-substituted aromatic CH); 4.06(q, J=7.0Hz, 2H, ethoxy-CH₂); 3.13(s, 3H, CH₃); 1.43(t, J=7.0 Hz, 3H,ethoxy-CH₃).

EXAMPLE 8

[0088] 2-(4-Ethoxyphenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine

[0089] Titanium tetrachloride (26 mL) was added to a stirred suspensionof 1-(4-ethoxyphenyl)-2-(4-methanesulfonyl-phenyl)-ethanone (75.0 g),N-amino-pyridazinium hexafluorophosphate (59.6 g) in DCM (1125 mL) atabout 20° C. N-Methyl-pyrrolidinone (23 mL) was added and TMEDA (50 mL)was added over a period of about 4 hours and the reaction mixture heatedat 40° C. for 4.5 hours. The reaction mixture was stirred at about 20°C. for about 2 hours and further TMEDA (93 mL) was added over about 15minutes. The mixture was stirred for about 18 hours and iodine (63 g)was added. After about a further 5 hours, IMS (55 mL) was added,followed by 3.3M hydrochloric acid (1125 mL) and the layers wereseparated. The organic extract was further washed with 3.3M hydrochloricacid (375 mL), aqueous sodium carbonate solution (20% w/v, 375 mL),aqueous sodium thiosulfate solution (20% w/v, 2×375 mL) and aqueoussodium chloride solution (3% w/v, 2×375 mL). The organic extract wasthen concentrated by distillation to a residual volume of about 450 mLand iso-octane (about 187 mL) was added at about 38° C. The resultantslurry was cooled to about 0-5° C. and filtered. The crude product waswashed with DCM/iso-octane (1:1, 2×150 mL) and iso-octane (400 mL),dried, and then dissolved in acetone (1200 mL). This solution was heatedto about 50° C. and treated with charcoal (19 g) for about 1 hour beforefiltering. The charcoal was washed with hot acetone (750 mL) and thecombined filtrates and washings were concentrated by distillation to aresidual volume of about 825 mL. Further acetone (375 ml) was added tothe concentrate, which was concentrated again to a residual volume ofabout 825 mL. Maintaining the temperature at about 50° C., water (450mL) was added over about 1 hour, causing the product to crystallise.After cooling the slurry to about 0-5° C. the product was isolated byfiltration, washed with chilled acetone/water (1:1, 2×150 mL), and driedin vacuo at 65° C. to give the title compound as a pale yellowcrystalline solid (63.6 g, 68.6%), spectroscopically identical to theproduct of Example 7.

EXAMPLE 9

[0090]2-(4-Ethoxyphenyl)-3-(4-methanesulfonyl-phenyl)-3,3a-dihydro-pyrazolo[1,5-b]pyridazine

[0091] Titanium tetrachloride (3.45 mL) was added to a stirred mixtureof 1-(4-ethoxyphenyl)-2-(4-methanesulfonyl-phenyl)-ethanone (10.0 g),N-amino-pyridazinium hexafluorophosphate (7.95 g) in dichloromethane(150 mL) at about 20° C. N-Methyl-pyrrolidinone (3.0 mL) was added atabout 20° C. TMEDA (6.7 mL) was then added over a period of about 4hours at about 20° C. After stirring the mixture for about 1 hour, asecond portion of TMEDA (12.3 mL) was added over about 20 minutes, andthe reaction mixture was stirred at about 20° C. for about 16 hours.

[0092] A sample of the reaction mixture was purified by mass-directedpreparative HPLC: Column: ODS-2 IK-5; 15 × 2 cm (5 μm) Detection: MassSpectroscopy (Micromass ZMD spectrometer) Flow rate: 8 mL/min Temp:Ambient water + 0.04% v/v MeCN + 0.04% v/v Time (min) TFA (%) TFA (%)  050 50 15 10 90 25 10 90

[0093] Fractions containing compound exhibiting m/z 396 were combinedand evaporated to dryness to give the title compound.

[0094]¹H-NMR (CDCl₃) δ7.88 (2H) d, J=8.3 Hz; δ7.59 (2H) d, J=8.8 Hz;δ7.39 (2H) d, J=8.3 Hz; δ6.81 (2H) d, J=8.8 Hz; δ6.74 (1H) m; δ5.83 (1H)m; δ5.37 (1H) m; δ4.74 (1H) m, δ4.59 (1H) d, J=10.8 Hz; δ4.00 (2H) q,J=6:8 Hz; δ3.04 (3H) s; δ1.39 (3H) t, J=6.8 Hz; MH⁺ 396.

1. A process for the preparation of a compound of formula (I)

and pharmaceutically acceptable derivatives thereof in which: R⁰ ishalogen, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxy substituted by one or morefluorine atoms, or O(CH₂)_(n)NR⁴R⁵; R¹ and R² are independently selectedfrom H, C₁₋₆alkyl, C₁₋₆alkyl substituted by one or more fluorine atoms,C₁₋₆alkoxy, C₁₋₆hydroxyalkyl, SC₁₋₆alkyl, C(O)H, C(O)C₁₋₆alkyl,C₁₋₆alkylsulphonyl, C₁₋₆alkoxy substituted by one or more fluorineatoms, O(CH₂)_(n)CO₂C₁₋₆alkyl, O(CH₂)_(n)SC₁₋₆alkyl, (CH₂)_(n)NR⁴R⁵,(CH₂)_(n)SC₁₋₆alkyl or C(O)NR⁴R⁵; with the proviso that when R⁰ is atthe 4-position and is halogen, at least one of R¹ and R² isC₁₋₆alkylsulphonyl, C₁₋₆alkoxy substituted by one or more fluorineatoms, O(CH₂)_(n)CO₂C₁₋₆alkyl, O(CH₂)_(n)SC₁₋₆alkyl, (CH₂)_(n)NR⁴R⁵ or(CH₂)_(n)SC₁₋₆alkyl, C(O)NR⁴R⁵; R³ is C₁₋₆alkyl or NH₂; R⁴ and R⁵ areindependently selected from H, or C₁₋₆alkyl or, together with thenitrogen atom to which they are attached, form a 4-8 membered saturatedring; and n is 1-4; which comprises oxidising under conventionalconditions the corresponding compound, or derivative thereof, of formula(II)

wherein R⁰ to R³ are as defined for formula (I) above.
 2. A processaccording to claim 1 wherein the compound of formula (II) is prepared bytreating an imine of formula (III) with a base and wherein the imine offormula (III) is prepared by reacting an ethanone of formula (V) with anN-aminopyridazinium salt of formula (IV).
 3. A process according toclaim 1 or 2 for the preparation of2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazineand pharmaceutically acceptable derivatives thereof which comprisesoxidising under conventional conditions the compound of formula (II)that is

or a corresponding derivative thereof. 4.2-(4-Ethoxyphenyl)-3-(4-methanesulfonyl-phenyl)-3,3a-dihydro-pyrazolo[1,5-b]pyridazine,or a derivative thereof corresponding to a pharmaceutically acceptablederivative of the compound of formula (I) of which2-(4-ethoxyphenyl)-3-(4-methanesulfonyl-phenyl)-3,3a-dihydro-pyrazolo[1,5-b]pyridazineis the direct precursor.
 5. An imine of formula (III)

wherein R⁰ is at the 4-position and is ethoxy; R¹ and R² are H; R³ ismethyl; and X⁻ is a counterion, or a derivative thereof whichcorresponds to a pharmaceutically acceptable derivative of the compoundof formula (I) of which the imine is a precursor. 6.1-(4-ethoxyphenyl)-2-[4-(methylsulfonyl)phenyl]ethanone or a derivativethereof which corresponds to a pharmaceutically acceptable derivative ofthe compound of formula (I) of which1-(4-ethoxyphenyl)-2-[4-(methylsulfonyl)phenyl]ethanone is a precursor.7. An N-aminopyridazinium salt of formula (IV)

wherein: R¹ and R² are independently selected from H, C₁₋₆alkyl,C₁₋₆alkyl substituted by one or more fluorine atoms, C₁₋₆alkoxy,C₁₋₆hydroxyalkyl, SC₁₋₆alkyl, C(O)H, C(O)C₁₋₆alkyl, C₁₋₆alkylsulphonyl,C₁₋₆alkoxy substituted by one or more fluorine atoms,O(CH₂)_(n)CO₂C₁₋₆alkyl, O(CH₂)_(n)SC₁₋₆alkyl, (CH₂)_(n)NR⁴R⁵,(CH₂)_(n)SC₁₋₆alkyl or C(O)NR⁴R⁵; and X⁻ is PF₆ ⁻. 8.N-Aminopyridazinium hexafluorophosphate.